In general, it is said that NAFLD includes simple steatosis (hereinafter, “SS”) and non-alcoholic steatohepatitis (hereinafter referred to as “NASH”), which is developed from SS. NASH has a possibility to progress to poor prognosis diseases such as cirrhosis, and hepatocellular carcinoma. However, at present, there are no useful diagnostic markers for diagnosing NAFLD. NAFLD is usually diagnosed by ultrasonography, but pathological findings of liver biopsy are necessary for its correct diagnosis. The liver biopsy imposes a heavy burden on patients and lacks convenience. Accordingly, it is unsuitable for medical examination of lifestyle-related diseases. If NAFLD is detected at an earlier stage, NAFLD can be immediately prevented from progressing and can be treated, which is, needless to say, very advantageous.
Regarding a kininogen, Japanese Unexamined Patent Application Publication No. 04-110660 (Patent Literature 1) discloses a liver disease diagnostic agent composed of a kininogen/calpain complex. Patent Literature 1 states that the complex diagnostic agent is useful for diagnosing liver diseases such as chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, hepatitis A, and fulminant hepatitis, but not NAFLD. Furthermore, there is no description about the use of full-length kininogen or a specific biological material derived from the kininogen as an NAFLD diagnostic marker.
C. Cordova, et al. (Non-Patent Literature 1) report on that the level of kininogen decreases in patients with chronic hepatitis or liver cirrhosis, compared to that in healthy individuals, but do not mention or suggest any relationship between hepatic steatosis (including NAFLD) and the kininogen.
Thus, a marker is desired for discrimination between, for example, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma that have been developed from NAFLD. A known marker of such a type is complement C4, which is a protein generated in the liver and present in the serum and gets involved in immunoreaction and prevention of infection. Japanese Unexamined Patent Application Publication No. 2006-300689 (Patent Literature 2), a report on the use of C4 as a liver disease marker, states that the marker can be detected in patients with chronic hepatitis or liver cirrhosis, but not in healthy individuals or that the marker can be detected in healthy individuals and patients with chronic hepatitis, but not in patients with liver cirrhosis. Patent Literature 2, however, does not mention the discrimination of healthy individuals, patients with NAFLD, and patients with chronic hepatitis, including ASCs of hepatitis virus, from one another. Furthermore, Japanese Unexamined Patent Application Publication No. 2006-308533 (Patent Literature 3) states that the presence or absence or the amounts of complement C4 and its partial peptides are different between healthy individuals and liver cancer patients and are therefore useful as markers for discriminating patients with liver cancer from healthy individuals. Patent Literature 3, however, does not mention the discrimination of healthy individuals, patients with NAFLD, patients with chronic hepatitis, and ASCs from one another at all.
Furthermore, Dumestre-Perard, et al. (Non-Patent Literature 2) report on a method for determining the results of treatment of chronic hepatitis caused by hepatitis C virus through monitoring the correlation between C4 and a rheumatoid factor during the process of treating with, for example, interferon or ribavirin, but do not mention the discrimination of healthy individuals, patients with NAFLD, patients with chronic hepatitis, and ASCs from one another at all.    Patent Document 1: Japanese Unexamined Patent Application Publication No. 04-110660    Patent Document 2: Japanese Unexamined Patent Application Publication No. 2006-300689    Patent Document 3: Japanese Unexamined Patent Application Publication No. 2006-308533    Non Patent Document 1: C Cordova, et al., “Hageman factor, high molecular weight kininogen, and prekallikrein in chronic liver disease”, J Clin Pathol, 39, 1003-1005, (1986)    Non Patent Document 2: Dumestre-Perard, et al., Clin Exp Immunol, 127, 131-136, (2002)